3,4-Methylenedioxymethamphetamine Activates Nuclear Factor- κB, Increases Intracellular Calcium, and Modulates Gene Transcription in Rat Heart Cells

3,4-Methylenedioxymethamphetamine (MDMA) is an illicit psychoactive drug that has gained immense popularity among teenagers and young adults. The cardiovascular toxicological consequences of abusing this compound have not been fully characterized. The present study utilized a transient transfection/dual luciferase genetic reporter assay, fluorescence confocal microscopy, and gene expression macroarray technology to determine nuclear factor-κB (NF-κB) activity, intracellular calcium balance, mitochondrial depolarization, and gene transcription profiles, respectively, in cultured rat striated cardiac myocytes (H9c2) exposed to MDMA. At concentrations of 1×10−3 M and 1×10−2 M, MDMA significantly enhanced NF-κB reporter activity compared with 0 M (medium only) control. This response was mitigated by cotransfection with IκB for 1×10−3 M but not 1×10−2 M MDMA. MDMA significantly increased intracellular calcium at concentrations of 1×10−3 M and 1×10−2 M and caused mitochondrial depolarization at 1×10−2 M. MDMA increased the transcription of genes that are considered to be biomarkers in cardiovascular disease and genes that respond to toxic indults. Selected gene activation was verified via temperature-gradient RT-PCR conducted with annealing temperatures ranging from 50°C to 65°C. Collectively, these results suggest that MDMA may be toxic to the heart through its ability to activate the myocardial NF-κB response, disrupt cytosolic calcium and mitochondrial homeostasis, and alter gene transcription

Comprehensive epigenomic profiling reveals the extent of disease-specific chromatin states and informs target discovery in ankylosing spondylitis

International audienceAnkylosing spondylitis (AS) is a common, highly heritable inflammatory arthritis characterized by enthesitis of the spine and sacroiliac joints. Genome-wide association studies (GWASs) have revealed more than 100 genetic associations whose functional effects remain largely unresolved. Here, we present a comprehensive transcriptomic and epigenomic map of disease-relevant blood immune cell subsets from AS patients and healthy controls. We find that, while CD14+ monocytes and CD4+ and CD8+ T cells show disease-specific differences at the RNA level, epigenomic differences are only apparent upon multi-omics integration. The latter reveals enrichment at disease-associated loci in monocytes. We link putative functional SNPs to genes using high-resolution Capture-C at 10 loci, including PTGER4 and ETS1, and show how disease-specific functional genomic data can be integrated with GWASs to enhance therapeutic target discovery. This study combines epigenetic and transcriptional analysis with GWASs to identify disease-relevant cell types and gene regulation of likely pathogenic relevance and prioritize drug targets

Young Australian consumers and the country-of-origin effect: investigation of the moderating roles of product involvement and perceived product-origin congruency

The effect that consumers’ country-related images have on their purchase decisions is known as the country-of-origin effect. Marketing researchers have thoroughly investigated COO effects in a range of contexts since the mid-1960s. However, since the 1980s it has been thought (e.g., Levitt, 1983; Ohmae, 1995) that consumer needs and wants are converging and that nation states are artificial and superficial entities of little value as quality indicators. The argument is that since the world is changing and because young consumers are used to seeing products from a variety of countries they do not have the country biases that the COO effect stipulates. Indeed, a recent study (Wong et al., 2008) on young Chinese consumers and the COO effect seems to confirm that young consumers no longer are influenced by the COO effect. The aim of this research is to investigate if and how the relationship between young Australian consumers’ product-country image and their product evaluations is influenced by two contextual variables: their product involvement and their perceived product-origin congruency. The research reports the results and relevant implications for research and practice

A genetics-led approach defines the drug target landscape of 30 immune-related traits

ISSN:1061-4036ISSN:1546-171